06 ANNUAL REPORT 06Centre for Molecular Biology

and Neuroscience (CMBN)

CMBNCentre for Molecular Biology and Neuroscience

P.O.Box 1105 Blindern |N-0317 Oslo | Norway

Phone: +47 22 85 14 95Fax: +47 22 85 14 88

cmbn-adm@medisin.uio.nowww.cmbn.no

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easy

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SUMMARY

SUMMARY

Looking back on 2006 – and on the way ahead In December 2006 the Centre received the good news that it will be continued for another 5 year period – until end 2012. In fact, the Centre passed the half time evaluation with flying colors. The report recognizes the high productivity of the Centre and concludes “……the Centre for Molecular Biology and Neu-roscience is well organized and contrib-utes importantly to provide better facili-ties for each of the eleven groups, which have complementary expertise in differ-ent molecular and neurobiological areas. All three evaluators ranked the research at the centre as exceptionally good.”

The positive outcome of the half time evaluation is a tribute to the devotion and enthusiasm of the entire staff associ-ated with the Centre – and also attests to the strong administrative and finan-cial support from the host institutions – the University of Oslo and Rikshospi-talet-Radiumhospitalet Medical Centre. The half time evaluation report provides CMBN with a vote of confidence that will serve as an important backing for the Centre’s activities and strategy to-wards 2012.

From CMBN I to CMBN IIThe CMBN was designed to elucidate select biological processes (including ge-nome instability, DNA damage and re-pair, glutamatergic transmission and ion transport, stem cells, brain development, and mechanisms of edema and infection) that are inextricably coupled to brain disease and the treatment thereof. The overriding aim was to build a knowledge base for new approaches to the treat-

ment of brain disease and age-related neurological impairment. In its second period (CMBN-II), the Centre will re-tain its strong focus on basic research. However, it will concentrate its efforts on analysis of disease mechanisms and on pursuing new directions for therapy that have been revealed through discov-eries and breakthroughs made in the Centre’s first period (CMBN-I). Thus the Work Program for 2007 – 2012 in-cludes in vitro approaches for drug de-sign and testing, and analyses of patient cohorts, particularly in contexts where the Centre has provided a strong experi-mental base for such endeavours.

The continuation of the Centre will al-low it to harvest the benefits of the major investments that were made in CMBN’s first period. These investments have translated into the generation of new experimental models (including a wide range of transgene animals), the intro-duction of new technologies (including multiphoton in vivo imaging, animal-PET, proteomics, and structural biol-ogy), and the establishment of a number of national and international networks that broaden the expertise and intellec-tual capital of the Centre.

The new building -”interaction through key technologies”The strategic preparation for CMBN-II coincided with the planning phase for the new building at Gaustad, close to Domus Medica. This building will be housing many technologies and infra-structure resources that are expected to stimulate biomedical research also out-side of the Centre, and far beyond the life expectancy of the Centre itself.

Specifically, the new building is meant to provide a link between the basic scientists and the clinical research en-vironments on the Gaustad campus and to serve as a resource and strategic as-set for the region’s biomedical research community at large. The technologies that will be established in the new build-ing will bolster the competitive advan-tage of the research community, add to existing and new core facilities and help increase the success rate for applica-tions to EU’s seventh framework pro-gram and other international funding bodies. CMBN will play an active role in building up the facilities as a common resource that will outlast by far the life time of the Centre.

The functions and technologies that will be allocated to the new building in-clude:

• High throughput tissue processing

• Proteomics/structure biology

• Imaging – including multiphoton imaging and PET/MR

• Neuro/bioinformatics

• Transgene technology/animal facilities

• Animal models (particularly in vivo models that will help facili-tate translational research)

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The Board of the University of Oslo decided in May 2006 that the building process should be initiated. It is essen-tial that this process now proceed as planned and that we will see no further delays. Once the building is completed it will allow for an “interaction through key technologies” that will boost the out-put of the Centre and of other research groups that stand to benefit from the new facilities.

2006: Scientific output The policy of the Centre is to publish its findings in leading peer-reviewed jour-nals. Accordingly, a large fraction of the more than 60 papers that emanated from the Centre in 2006 appeared in journals with very high impact such as EMBO Journal, Nature Reviews Microbiology, Neuron, Proceedings of the National Academy of Sciences USA and FASEB Journal. Space does not allow for a de-scription of the numerous discoveries and scientific advances that this long list of papers represents. Suffice to mention that the Centre has now reached most of the milestones that were embedded in the Work Program for CMBN I.

A main element in the Centre’s publi-cation strategy for 2006 was the prepara-tion of a Special Issue entitled Genome Dynamics and DNA Repair in the CNS. Most of the papers scheduled to appear in this Issue were published in electronic version in 2006 (the hard copy version of the Issue will be published in spring 2007). Dr. Vilhelm Bohr, who is affili-ated with CMBN as a Guest Professor, has played a central role in the compila-tion and editing of the Special Issue. His contribution is gratefully acknowledged.

The publication of the Special Issue is an important event in the life of the CMBN, not least because it directly addresses one of the concepts that motivated the establishment of the Centre: that knowl-edge of the mechanisms of DNA damage and repair could advance significantly our understanding of the mechanisms underlying neurodegenerative disease and brain ageing. In fact, the composi-tion of the CMBN reflects our vision that a better understanding of brain diseases - and new approaches to the treatment of these - will arise by bringing together expertise in DNA repair with expertise in neurobiology. While the development of new therapies is a long term goal, the Special Issue attests to the fact that ge-nome instability and DNA repair mecha-nisms are now centre stage in the field of neurological research. Thus we feel comfortable with the above vision, set forth in our original application in 2002.

Meetings and symposia 2006The Special Issue described in the prece-ding paragraph was based on a major international meeting, hosted by the CMBN. The meeting – entitled “The First Genome Dynamics in Neuroscience Meeting” (GDN) - took place in Oslo in April 2006 and included more than 20 lecturers from abroad. The GDN event was the first international meeting to address genome instability and DNA re-pair in the context of neuroscience and ageing in a multidisciplinary setting. The second GDN meeting is already sched-uled to be held in California, USA, in 2008.

The CMBN also organized a number of other international meetings in 2006, all of which were open for participants outside the Centre. “The first glial end-foot meeting: Physiology and patho-physiology at the brain-blood interface” was arranged in June 2006 and marked the initiation of a Storforsk project on this topic. In June 2006 CMBN research-ers also arranged two other meetings: a workshop on “Databasing the brain”, and the “Erling Seeberg Symposium on DNA Repair”. The latter symposium commemorated the late Erling Seeberg who was one of the founding fathers of the CMBN.

October 2006 saw the organization of two other international CMBN meet-ings: a workshop on comparative micro-bial genomics and a symposium entitled “Glutamatergic mechanisms: Implica-tions for brain disease”.

A complete list of meetings and symposia is found elsewhere in this annual report.

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SUMMARY

Tone Tønjum

Ole Petter Ottersen

Prizes and awards 2006The symposium on “Glutamatergic mechanisms: Implications for brain dis-ease” coincided with the handing out of Jahre Prizes to two CMBN scientists: Jon Storm-Mathisen (recipient of the senior prize) and Farrukh Chaudhry (recipient of the young investigator award). These prestigious prizes represent a welcome recognition of the contributions of these researchers to the field of glutamate re-search. The CMBN was also proud to learn that His Majesty the King’s gold medal 2006 for the best doctoral thesis at the Faculty of Medicine was awarded to Tonje Davidsen at CMBN.

Other events in 2006A new centre of excellence system – Centres for Research-based Innova-tion – was established in 2006. One of the appointed Centres will be headed by CMBN group leader Stefan Krauss.

On a different note, 2006 saw the estab-lishment of the first animal-PET facility in Norway. The PET facility is run by the CMBN through Jan Bjaalie’s laboratory (http://www.nesys.uio.no/pet/).

Jan Bjaalie is currently on leave of ab-sence from the CMBN after having been appointed as the Head of International Neuroinformatics Coordinating Facil-ity (INCF) located at the Karolinska Institute in Sweden for the period 2006 – 2007. Trygve Leergard has taken over as group leader for this period.

It should also be mentioned that Peter Agre’s term as CMBN guest professor has been renewed for 2007 – 2009. Peter Agre’s active support of the Centre has been invaluable and we are glad to have him on board for a new period.

Finally we would like to take this oppor-tunity to thank the Norwegian Research Council and all the other funding bodies that have supported the activities of the CMBN in 2006. We are also grateful to the administrative staffs of the Institute of Basic Medical Sciences and the Insti-tute of Microbiology for their excellent assistance in administrative matters. Our thanks are extended to our host institu-tions: the Faculty of Medicine and Facul-ty of Mathematics and Natural Sciences, University of Oslo, and Rikshospitalet-Radiumhospitalet Medical Centre which have provided optimal working condi-tions for CMBN ever since its inception in 2002.

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SUMMARY

TOC

TABLE OF CONTENTS

SUMMARY ..................................................................................... 2

MIDTERM EVALUATION ................................................................ 6

HIGLIGHTS ...................................................................................... 8

AWARDS AND DOCTORAL DEGREES ......................................... 9

NETWORKS ................................................................................... 10

EDUCATION AND INTERACTION ACTIVITIES .................................. 11

COMMERCIALIZATION ................................................................... 15

MEDIA COVERAGE ........................................................................ 15

PUBLICATIONS .............................................................................. 16

ABOUT CMBN AND THE GROUPS ................................................ 19

FUNDING AND COSTS ................................................................ �1

CMBN PERSONNEL AND ASSOCIATED MEMBERS .................... �1

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MIDTERM EVALUATION

MIDTERM EVALUATION

The Research Council of Norway deci-ded in December 2006 after a compre-hensive midterm evaluation to continue its support to CMBN.

The international scientific evaluation committee concluded as follows in their evaluation of CMBN (http://www.forskningsradet.no):

“The centre for Molecular Biology and Neuroscience is chaired by professor Ole Petter Ottersen, a well-known neuro-scientist and there are altogether eleven principal investigators representing diff-erent areas of cellular and molecular neuroscience and molecular biology. The group leaders are as follows: professor Jan Bjaalie (Neuroinformatics), professor Magnar Bjørås, professor Niels Danbolt (Neuroanatomy), professor Arne Klung-land, professor Michael Koomey, profe-ssor Stefan Krauss, professor Ole Petter Ottersen, associate professor Torbjørn Rognes, professor Johan Storm (Cellular Neurophysiology), professor Jon Storm-Mathisen (Synaptic transmission) and professor Tone Tønjum.

The ambition of this centre has been to facilitate the interaction between differ-ent research groups at University of Oslo, working with molecular techniques whether within the nervous system or in other areas. The ambition of the centre is to broaden the interaction between different subdisciplines and expand the methodology platforms available to each researcher within the centre. The overall goal has thus been to facilitate the in-teraction to allow each research group to apply a broader methodological rep-ertoire with a focus on molecular (e. g. DNA repair) and cellular function as well as mechanisms to address a num-ber of brain diseases and to find thera-peutic targets at the molecular and cel-lular level.

Research achievements at the time of evaluationThe Centre for Molecular Biology and Neuroscience has been very active and reports no less than two hundred papers in refereed journals from July 2002 until March 2006. A large number of the articles are published in high impact journals in the different fo-cus areas of the principal investigators extending from DNA repair to neurologi-cal diseases and mechanisms of synap-tic transmission.

The different areas have been divided into work-packages led by different group leaders. The first represents neuroinformatics (Jan Bjaalie). The centre has contributed importantly with the devel-opment of databases, extensive tool de-velopment and image registration and has taken on an international leader role in this aspect. The work-package in bioinformatics aims at coordinating neuro - and bioinformatics. The focus of this group has been on DNA repair, bacte-rial components, genome maintenance, mammalian transporter channels and the identification of single nucleotide polymorphisms. Jon Storm Mathisen and Ole Petter Ottersen have had a pio-

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neering role in identifica-tion of the different com-ponents in glutamatergic

synaptic transmission that is the major excitatory trans-

mitter in the nervous system. At the same time glutamate

can give rise to toxic reactions if released excessively under pathologi-

cal conditions like stroke. Not only neu-rons but also glial cells have been found to release glutamate. The subsequent work-package on neuronal ion channels (Johan Storm) is focused on the role of different subtypes of potassium channels, not only during physiological conditions, but also during neurological disease. Potassium channels play a major role in the nervous system and no less than ten mutations in potassium channels have been identified and are known to lead to disease states (e. g. epilepsy). The different potassium channels are also potential targets for drugs. DNA damage and repair and genome instability are relevant not least in the context of

neuroscience and aging. Novel DNA repair mechanisms have been identi-fied within this work-package and are clearly of importance for neurodegenera-tive diseases of different kinds and its molecular mechanism. Another work-package deals with the homeostasis in the brain and the control of extracellular potassium, transport of water and brain oedema. It represents another major

area dealt with by the chairman in inter-action with Peter Agre, Nobel laureate and the discoverer of water channels. Work-package 7 (M. Koomey) deals with meningococcal genome dynamics is one area and the host - microbe inter-action, which clearly is important for an understanding of the pathogenetic mechanisms. It is concerned with both interaction with the neuronal tissue and the glial responses. Stem cells and repair and memory formation are also a focus for the consortium.

From the above follows that the centre provides a very broad field of expertise and methodology and it appears that it has managed to create an efficient and stimulating interaction between the eleven group leaders that most likely had not occurred without the formation of the Centre of Excellence. Clearly the net result is a very productive and high profile environment within a number of related and important areas of research.

The centre has a very extensive inter-national exchange with leading research groups. The research training is of high quality and clearly of international stan-dard. The environment has attracted a number of foreign researchers, postdocs and doctoral students and in addition a number of guest professors have worked at the centre for shorter or longer periods including Peter Agre.

Organisational and administrative aspectsThe centre is coordinated by Ole Pet-ter Ottersen with Tone Tønjum as co- director. They report to the board for the centre appointed by the President of the University of Oslo. The board in turn reports to the top management of the university and ‘Rikshospitalet-Radium-hospitalet’.

Rather than creating a separate admin-istration at the Centre of Excellence, the administrative facilities already availa-ble in the different departments have been utilised. Although being in different buildings (the distance is not too great) this form of distributed governance has apparently worked well for the centre.

The interaction between the host institution and the centre appears to have worked smoothly. The chair of the centre has previously been dean at the medical faculty. He has done a very good job as coordinator and has at the same time continued to play a major role scientifically.”

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HIGHLIGHTS 2006

Small animal imaging unit (PET/CT) at CMBNFollowing nearly 2 years of planning and testing, new dedicated high end scanners for small animal imaging, microPET and microCAT, are now in routine use at the University of Oslo.

The decision to locate a small animal imaging unit at the Center for Molecu-lar Biology and Neuroscience (CMBN) was made by the Faculty of Medicine in 2004. CMBN group leader, Professor Jan Bjaalie, was appointed as responsi-ble for establishing the unit. A contract with Santax Medico AS (Denmark)/CTI Molecular Imaging (currently Siemens) (USA) was signed in 2004 and the Con-corde microPET Focus 120 and Imtek microCAT II scanners were delivered in May 2005. Dr. Frode Willoch served as key advisor throughout the process of establishing the unit. He has also been in charge of the initial validation and is the lead operational scientists in the unit. Dr. Dag Sørensen at the Department of Comparative Medicine, Rikshospitalet, has provided the space for the equip-ment as well as valuable advice with the

establishment of the animal procedures. Daily operations of the units are lead by Chief engineer, Dr. Hong Qu. Drs. Wil-loch and Bjaalie supervise one Ph.D. stu-dent, Trine Hjørnevik, who has an M.Sc. in Physics.

The PET radiopharmaceutical chemistry group of Associate Professor Gjermund Henriksen is closely linked to the imag-ing unit. All projects using tracers other than FDG are based on collaborations with Dr. Henriksen, who also takes part in the project planning and running of the experiments.

The establishment and running of the Small animal PET research are sup-ported by the CMBN group leaders. The CMBN Director, Professor Ole Petter Ottersen, has provided continuing fol-low up with regard to development of new scientific concepts as well as fund-ing initiatives. For more information, see: http://www.nesys.uio.no/pet/.

International Neuroinformatics Coordinating Facility (INCF) The Norwegian Node of INCF has rec-ently been established at CMBN under coordination by group leader Johan Storm.

INCF is an international organization aimed at promoting the global devel-opment of neuroinformatics, that is, the use of methods from computer sci-ence, mathematics and statistics to strengthen neuroscience research. The main secretariat of INCF is hosted by Karolinska Institutet in Stockholm, with professor Jan G. Bjaalie as execu-tive director. For more information, see http://www.incf.org/ .

As a first step in establishing the node we are presently informing the main neuro-science environments in Norway about INCF and the opportunities INCF offer for Norwegian neuroscience. One of the main goals in 2006 is to establish a suf-ficient strategy on how the INCF node should operate in Norway. In particular we want to get input on how one most efficiently can use the resources allo-cated to INCF Norway to strengthen the use of neuroinformatics methods.

Combined PET/CT examination of rat brain showing focally increased uptake of 18F-fluoro deoxyglucose metabolism after inoculation with glioma cells.

PET examinations showing changes in 18F-flu-oro deoxyglucose uptake in response to sensory stimulation.

HIGLIGHTS

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AWARDS AND DOCTORAL DEGREES

Awards 2006

Anders Jahre’s awards to Jon Storm-Mathisen and Farrukh ChaudhryProfessor and group leader Jon Storm-Mathisen and CMBN guest professor Farrukh Chaudhry were awarded Anders Jahre’s prizes for medical research in 2006. The prizes are awarded for their research on signalling molecules in the brain and on protein structures, and are the most prominent biomedical research awards in the Nordic countries.

Gold medal to Tonje Davidsen The University of Oslo decided that His Majesty the King’s gold medal 2006 for the best doctoral thesis at the Faculty of Medicine be awarded to Tonje Davidsen at CMBN. The doctoral degree was supervised by CMBN co-director and group leader Tone Tønjum.

Doctoral degrees 2006Petter Angell Olsen defended his PhD thesis with the title: “Targeted sequence alteration in the genomes of mammalian cells mediated by oligonucleotides”. The candidate was supervised by group leader Stefan Krauss.

Fulvio Celsi defended his PhD thesis at The University of Tor Vergata (Roma) with the title; “Calcineurin role in pathogenesis of Alzheimer’s Disease”. The candidate was co-supervised by CMBN director and group lead-er Ole Petter Ottersen and CMBN researcher Reidun Torp.

Runhild Gammelsæter defended her PhD thesis with the title: “Amino acid signaling in islets of Langerhans”. The candidate was supervised by senior researcher Vidar Gundersen.

Cecilia Løvold defended her PhD thesis with the ti-tle: “Covalent modifications of Neisseria gonorrhoeae Type IV pili with phosphoethanolamine and phos-phocholine: Roles of the PptA protein and ancillary factors”. The candidate was supervised by group leader Michael Koomey .

Elise Rundén Pran defended her PhD thesis with the title: “Intra- and extracellular signaling pathways un-derlying cell death in hippocampus”. The candidate was supervised by CMBN director and group leader Ole Petter Ottersen.

Anna Thoren defended her PhD thesis at The Göte-borg University with the title: “Astrocyte metabolism following focal cerebral ischemia”. The candidate was co- supervised by CMBN Director and group leader Ole Petter Ottersen.

Jo Kristian Utvik defended his PhD thesis with the title: ”Protein interactions at the glutamate synapse”. The candidate was supervised by CMBN director and group leader Ole Petter Ottersen. Svend Davanger acted as co-supervisor.

Jon Storm-MathisenFarrukh Chaudhry

Tonje Davidsen

AWARDS AND DOCTORAL DEGREES

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NETWORKS

Gaustad Neuroscience Network (GNN), which was established at the initiative of CMBN, is a network that aims at linking basic science and clini-cal research at Gaustad. This initiative is a multidisciplinary action and addresses all aspects of neuroscience represented on the campus. The goal is to heighten the awareness of activities, competence and resources available locally, in order to elicit new collaborations, and to in-crease the output from ongoing research. The ambition is that GNN should foster a neuroscience research environment at the highest international level. New funding will have to be generated for GNN research activities, and in this con-text it is also notable that the Research Council of Norway has established a new funding source, NevroNor, which will support neuroscience research at the national level.

CMBN contributes to GNN by org-anizing meetings and providing finan-cial and logistical support for workshops and meetings. CMBN also covers a 20% position for a researcher that acts as a liaison officer between the clinical and basic research departments. GNN con-tributions and activities in 2006 included the organization of the globally attend-ed Genome Dynamics in Neuroscience (GDN) meeting in April 2006, participa-tion at the NCoE / WIRED meeting in June 2006 and hosting a seminar jointly organized between Rikshospitalet- Radiumhospitalet Medical Centre and Ullevål University Hospital at Gaustad.

International networksNordic Centre of excellence (NCoE) for Research in Water Imbalance Related Disorders (WIRED). Coordinator is CMBN director Ole Petter Ottersen. This Network is composed of four research teams from Norway, Sweden and Denmark plus an associated node in Finland.

Nordic Centre of excellence (NCoE) in Neurodegeneration, with CMBN group leaders Johan Storm and Arne Klungland as project partners. This Network is composed of 11 research teams from Sweden, Finland, Denmark and Norway.

NorFa Network of stem cell and regenerative medicine with CMBN group leader Stefan Krauss as coordinator.

EU project under the Sixth Framework Program (Specific Targeted Research or Innovation Project, STREP) on “Glutamate Receptor Interacting Proteins As Novel Neuroprotective Targets (GRIPANNT)” coordinated by the director of CMBN Ole Petter Ottersen. This EU network is composed of 10 partners from Poland, France, England, Denmark and Norway.

EU project under the Sixth Framework Program, Integrated Project “DNA damage response and repair mechanisms”, with CMBN group leaders Magnar Bjørås, Arne Klungland, Torbjørn Rognes as partners.

EU project under the Sixth Framework Program (STREP) on “Targeted sequence alteration”. Coordinator is CMBN group leader Stefan Krauss.

EU project under the Sixth Framework Program (STREP) on “Effect of genetic variation in Mycobacterium tuberculosis on vaccine escape and the acquisition of drug resistance (TBadapt)” with CMBN assistant director and group leader Tone Tønjum as partner. This EU network is composed of 11 partners from the Netherlands, United Kingdom, France, South Africa, Mexico, Vietnam and Norway.

EU project under the Sixth Framework Program (ESF “Eurostells”) international stem cell network. Coordinator is CMBN group leader Stefan Krauss.

EU project under the Fifth Framework Program (Marie Curie Training Site) in: Basic mechanisms of aminoacid neurotransmission (BAMAN). Coordinator is CMBN group leader Jon Storm-Mathisen.

EU project under the Sixth Framework Program (Marie Curie actions – Host fellowships for Early Stage Research Training) in: Cooperation in Research and Training for European Excellence in the Neurosciences (CORTEX). Partner is director of CMBN Ole Petter Ottersen.

GlobHel “Tuberculosis in the 21st century”, global network on advanced tuberculosis research sponsored by the Research Council of Norway. Co-partner is assistant director of CMBN Tone Tønjum, on the impact of genome instability.

FEMS - Secretary General for the Federation of European Microbiology Societies (FEMS) for 2006-2009 is held within CMBN (T. Tønjum).

The Chief Editorship of “Neuroscience” - the official journal of the International Brain Research Organization (IBRO) - lies within the Centre (Ole P. Ottersen).

NETWORKS

EDUCATION AND INTERACTION

ACTIVITIES 10

EDUCATION AND INTERACTION ACTIVITIES

Central elements of the Centre’s plan of activities are teaching and academic interactions. The plan also includes internal cooperation between the 11 groups of researchers as well as the further development of the Centre’s relations with external partners.

Research courses and lecturesAs part of the CoE Programme, the CMBN has undertaken to provide teaching for PhD students and post-doctoral fellows. The Centre is part of the Research School (“Forskerskole”) curriculum established by the University of Oslo in 2004. The CMBN Research school is headed by group leader Tone Tønjum. The following seminars were held in 2006:

The second Norwegian Transgenic Animal Forum was arranged at Tyrifjord Hotel, Vikersund, 23-24 March 2006.

The primary goal of the forum was to strengthen the scientific collaboration in the field of mouse transgene technology and to discuss how this technology

should be made available to the biomedical research community in Norway.

The First Genome Dynamics in Neuroscience (GDN) meeting took place on 26 - 29 April 2006 at The National Hospital. The Genome Dynamics in Neuroscience (GDN) meeting in April 2006

was the first international meeting to address genome instability and DNA repair in the context of neuroscience and ageing in a multidisciplinary setting.

Mechanisms for genome variation, adaptation and maintenance are a necessity to ensure cellular fitness and survival in changing environments. The objective of

the meeting was to highlight key aspects of DNA damage and repair in ageing and the pathogenesis of neurological disease, and to improve our understanding of how nerve cells communicate in the healthy and diseased brain. The topics addressed are relevant for neurological pathogenesis, genome instability and maintenance, stem cell biology, brain development, prokaryotic model systems and synaptic communication. The long-term goal is to identify new approaches for the treatment of brain disease and age-related neurological impairment. Added value from the meeting materialized in the production of a Special issue entitled “Genome dynamics in neuroscience” in the IBRO journal Neuroscience, encompassing 25 reviews and original articles by outstanding scientist from all parts of the world.

The Erling Seeberg Symposium on DNA Repair took place in Bodø and Henningsvær in Lofoten from 28 May to 2 June, 2006. One of the motivations for organizing this meeting was to honour Erling Seeberg. He had made many important and novel contributions to the field of biology in general and DNA repair and mutagenesis specifically. Erling Seeberg played a central role in the establishment of CMBN in 2002.

EDUCATION AND INTERACTION

ACTIVITIES 11

The first glial endfoot meeting, Physiology and pathophysiology at the brain blood interface, took place in Oslo, 6-7 June 2006.The meeting was organized jointly by WIRED and the Centre for Molecular Biology and Neuroscience (www.cmbn.no/wired), The meeting highlighted re-cent advances in our understanding of the physiology and pathophysiology of astrocytes, with focus on the perivascu-lar endfeet and their role in regulating exchange of water, gases, and metabo-lites at the brain blood interface.

Minisymposium: Neuroendocrine Sig-nalling by Amino Acids - New Deal in Diabetes? Oslo 14 June Professor Dr. Gudrun Ahnert-Hil-ger from AG Funktionelle Zellbiologie, Charité-Universitätsmedizin Berlin, Ger-many , held her lecture on the topic:

Regulation of vesicular transmitter uptake by heterotrimeric G proteins

Professor Dr Patrik Rorsman from Oxford Centre for Diabetes, Endocrionology and Metabolism (OCDEM), University of Oxford, UK, held his lecture on the topic:

GABA and the control of pancreatic islet function: studies in man and rodents

The second Databasing the brain workshop took place on 25-27 June 2006 at the Soria Moria conference center in Oslo. The overall objective of the workshop was to accelerate existing research and development efforts in the field of neu-roscience databasing. The workshop brought together scientists in the field of brain databasing, neuroscientists, rep-resentatives of SMEs, as well as journal editors and other representatives of jour-nals.

A Comparative Microbial Ge-nomics Workshop was organized in

Oslo on 16-20 October 2006 by associ-ate professor David W Ussery from the Centre for Biological Sequence Analysis (CBS) at the Technical Uni-versity of Denmark (DTU), and others.The workshop was designed to enable participants to use comparative genomic tools through lectures and hands-on practicals to extract biological meanings and discover novel genes from the vast amount of genomic data and solving problems of their research interest. The workshop also served as a platform for participants to establish multidisciplinary collaborations in comparative genomics research among various groups of scientists and researchers at national and international level.

The First Norwegian Microbiology Meeting for junior scientists was ar-ranged at Geilo on 22-24 October 2006.The NoMi-06 meeting was the first in a biannual series of meetings that seeks to gather junior scientists, post-docs, and Ph.D. students working in Norwegian institutions and companies in the area of microbial biology. This first meeting was limited to 60 participants from all regions of Norway and was organized by the FUGE platform CAMST (Consor-tium of Advanced Microbial Science and Technology) and the University of Oslo.

CMBN International Symposium & Jahre Lectures was held in Oslo 12-13 OctoberThe symposium Glutamatergic Mecha-nisms: Implications for Brain Disease was arranged in Oslo on 12-13 October. The Jahre lectures and award ceremony took place the same days.

In addition to seminars, CMBN also contributes to the Faculty of Medicine’s PhD educational program, with group leader Arne Klungland who is responsible for two one week laboratory courses (“Basic Methods in Molecular Biology”) for PhD students, including national and international students.

CMBN PhD group activities 2006The PhD student group tries to meet a couple of times each semester, to dis-cuss science, inform about the PhD programme and new acquisitions of equipment and technologies at CMBN. The group also promotes collaborative projects within the Centre, learn about each others work, and last, but not least engage in various kinds of social activi-ties (http://www.cmbn.no/phd/). All the CMBN departments have hosted a group meeting after the PhD student group’s establishment.

In March 2006 Arne Klungland, Profes-sor at the department of Molecular Bi-ology, gave a talk with the title “Trans-genic or gene targeting?” In May, Willy Fjeldskaar, Professor and chief scientist at the International Research Institute of Stavanger (IRIS), visited us to give a talk entitled “Is Darwin’s theory a good ex-planation for the nature’s complexity?” In October we had invited Professor Sis-sel Rogne from The Norwegian Biotech-nology Advisory Board. The topic of her talk was the proposed law on Norwe-gian stem cell research, giving comments and trying to define the terms research, method development, life, moral, ethics, chimeras, human/animal, stem cells and their potential and serious disease. These three scientific meetings were held in the department of Molecular Biology at the Rikshospitalet-Radiumhospitalet Medi-cal Centre. After the talks we had discus-sions and refreshments were served.

The PhD students also participated in CMBN lectures and seminars, and some of us joined the CMBN team in Holmen-kollstafetten. For 2007 we hope to con-tinue the scientific meetings throughout the year, and also arrange some social activities. The organization committee welcomes new members.

EDUCATION AND INTERACTION

ACTIVITIES

12

Guest ProfessorsThe recruitment of “Guest Professors” is an important element in the Centre’s strategy for academic cooperation. This cooperation is funded both through the Centre’s CoE grant and through external funds for which special applications are made for appropriate purposes. In 2006 the following four CMBN “Guest Pro-fessors” were formally appointed:

Peter Agre, Professor and Nobel Prize winner in Chemistry, 2003, Johns Hop-kins University, Baltimore, USA, now at Duke University. Funded by CMBN.

Vilhelm Bohr, Chief of Laboratory of Molecular Genetics, National Institute on Aging, NIH, Baltimore. Funded by CMBN.

Farrukh A. Chaudhry, Associate pro-fessor / group leader at the Biotechnol-ogy Centre, University of Oslo. Funded by CMBN.

Pål Falnes, Professor at the Institute of Molecular Bioscience, University of Oslo. Funded by CMBN.

Shankar Subramaniam, Professor, University of California at San Diego & San Diego Supercomputing Center. Funded by CMBN.

Dave Ussery, Associate professor in the Centre for Biological Sequence Analysis, Technical University of Denmark. Fund-ed by EMBIO at the University of Oslo.

CMBN seminars/guest lecturersAltogether, 14 CMBN seminars were held in 2006 with high-profile research-ers from abroad as specially invited lecturers. These guest lectures were ar-ranged on the initiative of the Centre management or group leaders. CMBN seminars are open to all and are widely announced.

Postdoc Ken Howard at the Depart-ment of Molecular Biology, University of Aarhus, gave his guest lecture on Thurs-day, 12 January 2006 on the topic: Small interfering RNA delivery and gene silencing using nanocarrier systems

Professor Vilhelm A. Bohr, chief, Labo-ratory of Molecular Gerontology, Na-tional Institute on Aging, NIH, US, gave his guest lecture on Wednesday, 25 Janu-ary 2006 on the topic: Oxidative DNA damage processing and changes with aging

Professor Bernd Epe, Institute of Phar-macy, University of Mainz, Germany, gave his guest lecture on Thursday, 9 February 2006 on the topic: Endogenous oxidative DNA base damage and its consequences

Professor Valina Dawson, Department of Neurology, The Johns Hopkins Uni-versity School of Medicine, USA, gave her guest lecture on Tuesday 28 Febru-ary 2006 on the topic: Genetic Clues to Unravel the Mystery of Parkinson’s Disease

Chris Tang, Imperial College, London, UK, gave his guest lecture on Tuesday 2 May 2006 on the topic: Interactions of N. meningitidis with the complement system

Peter Agre

Vilhelm Bohr

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Philip Beart, Howard Florey Institute, University of Melbourne, Australia, gave his guest lecture on Tuesday 12 September 2006 on the topic: Astrocytes and neuroprotection: mechanistic insights into the roles of glutamate transporters and hypoxiainducible factor (HIF)

Keiko Shimamoto, Suntory Institute for Bioorganic Research, Osaka, Japan, gave his guest lecture on Tuesday 12 September 2006 on the topic: Synthesis and Characterization of Novel Blockers to Probe Glutamate Transporter Functions

Assistant Research Professor Fan Meng PhD, Microrarray Laboratory, Psychiatry Department and Molecular and Behavioral Neuroscience Institute, University of Michigan, gave two guest lectures on Thursday 28 September 2006 on the topics: First lecture: Knowledgebased analysis of genomewide SNP scanning data and second lecture: GeneChip data analysis: the trick is in the probe sets

Dr. Lars Juhl Jensen, staff scientist at EMBL in Heidelberg, gave his guest lec-ture on Wednesday 25 October 2006 on the topic: Crossspecies data integration

The Centre’s lecture series for 2006 was supplemented by seminars under the auspices of affiliated units in the two host institutions (UiO and RR-HF). In addition there were open lectures under the auspices of each individual group at the Centre.

CMBN scientific retreatThe annual CMBN retreat was held at Hafjell. The Centre and its 11 research group were present with nearly 100 participants from the scientific, technical and administrative staff.

This annual CMBN retreat with lectures, workshops and discussions at Hafjell contributed to enhanced awareness and interactions between the research groups, not the least promoted by very interactive poster sessions (organized as guided tour / tutorials) and discussions.

Kim Q Do, PhD, privat-docent, Center for Psychiatric Neuroscience, Lausanne University, Switzerland, gave her guest lecture on Tuesday 9 May 2006 on the topic: Schizophrenia: redox dysregulation as vulnerability factor; from basic to clinical perspectives

James Fallon, professor of Anatomy and Neurobiology, University of California, USA, gave his guest lecture on Thursday 24 August 2006 on the topic: Imaging Genetics and the Neuroanatomy of Affective and Thought Disorders

Dr Manuel S. Malmierca, Laboratory for the Neurobiology of Hearing, The Institute of Neuroscience of ‘Castilla y Leon’ (INCyL), Faculty of Medicine, University of Salamanca, Spain, gave his guest lecture on Tuesday 25 July 2006 on the topic: The inferior colliculus: A key centre for auditory processing in the midbrain

Randi G. Syljuåsen, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark, gave her guest lecture on Tuesday 29 August 2006 on the topic: Cell cycle checkpoints induced in the absence and presence of ionizing radiation

Prof Jean-Pierre Changeux, Collège de France and l’Institut Pasteur, France, gave his guest lecture on Wednesday 27 September 2006 on the topic: The role of brain nicotinic receptors in reward and cognition

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COMMERCIALIZATION

In accordance with the agreements relating to the Centre, the commercialisation of research results emanating from the Centre is an important element in its future funding. The CMBN commercialization portfolio consisted in 2005 of two projects supported by Birkeland Innovation, which is the Technical Transfer Office (TTO) owned by The University of Oslo. Our Centre is also a partner in two spin off companies.

Sencel Bioinformatics founded in June 2001.The Company provides superior software tools to aid in genetic and gen-omic research and diagnostics. The name of the company stems from the mission to make sense of genetic data at an acceler-ated speed (www.sencel.com)

SiRNASENSE A/S founded in Decem-ber 2004. This is a company that aims at developing Anti-sense Therapeutics, RNA/SiRNA for pharmaceutical thera-peutics.

Stem Cell Based Tumor Therapy (Cen-tre for Research-based Innovation). The main objective for the Centre for Re-search-based Innovation (CRIs) is to en-hance the capability of the business sec-tor to innovate by focusing on long-term research based on forging close alliances between research-intensive enterprises and prominent research groups. The Centre will be headed by CMBN group leader Stefan Krauss.

COMMERCIALIZATION

MEDIA COVERAGE

MEDIA COVERAGE

The Centre has invested a great deal in popular-scientific publicising – both in Norway and abroad. A survey can be found on the Centre’s Web page www.cmbn.no. The Centre’s research has on numerous occasions been referred to in the main Norwegian daily newspapers. CMBN has made active contributions to the “Research Days” (sponsored by the Research Council) and participated in a number of radio and TV programmes.

CMBN’s web pages are continually up-dated with media events relating to the Centre and our different activities (web page responsible: CMBN group leader Torbjørn Rognes). Our media contact is CMBN group leader Jon Storm- Mathisen.

After having published an article in Nature (Ragnhildur Káradóttir, Pauline Cavelier, Linda H. Bergersen and David Attwell (2005) NMDA receptors are ex-pressed in oligodendrocytes and activated in ischaemia. Nature, 438, 1162-1167), Linda H. Bergersen told Uniforum (Janu-ary 2006) that she felt like she had won the Olympic medal in 4x100 meters.

Photo: Martin Toft | Uniforum

15

PUBLICATIONSJANUARY 06 – DECEMBER 06Abstracts not included

High impact papers (impact factor >6.0, ac-cording to ISI 2005) are indicated by *

1. Adzhubei AA, Lærdahl JK, Vlasova AV (2006) preAssemble: a tool for automatic sequencer trace data processing. BMC Bio-informatics, 7, 22.

2. *Alseth I, Rognes T, Lindback T, Solberg I, Robertsen K, Kristiansen KI, Mainieri D, Lillehagen L, Kolsto AB, Bjoras M.(2006) A new protein superfamily includes two novel 3-methyladenine DNA glycosylases from Bacillus cereus, AlkC and AlkD. Mol Microbiol. 59:1602-9. (Impact 6,2)

3. Amarzguioui M, Peng Q, Wiiger MT, Va-sovic V, Babaie E, Holen T, Nesland JM, Prydz H. (2006) Ex vivo and in vivo de-livery of anti-tissue factor short interfering RNA inhibits mouse pulmonary metastasis of B16 melanoma cells. Clin Cancer Res. 12:4055-61.

4. Ambur OH, Frye SA, Tønjum T (2006) A new functional identity for the DNA up-take sequence in transformation and its presence in transcriptional terminators. J Bacteriol. 2006 Dec 21; [PMID: 17194793, Epub ahead of print]

5. Bergersen LH, Storm-Mathisen J (2006) Tidsskr Nor Laegeforen. 126:3253.

6. Bergersen LH, Thomas M, Johannsson E, Waerhaug O, Halestrap A, Andersen K, Sejersted OM, Ottersen OP (2006) Cross-reinnervation changes the expression pat-terns of the monocarboxylate transporters 1 and 4: An experimental study in slow and fast rat skeletal muscle. Neuroscience 138:1105-13.

7. *Biskup S, Moore DJ, Celsi F, Higashi S, West AB, Andrabi SA, Kurkinen K, Yu SW, Savitt JM, Waldvogel HJ, Faull RL, Emson PC, Torp R, Ottersen OP, Dawson TM, Dawson VL (2006) Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol.60:557-69. (Impact 8.7)

8. Bjørnsen LP, Eid T, Holmseth S, Danbolt NC, Spencer DD, de Lanerolle NC (2006) Changes in glial glutamate transporters in human epileptogenic hippocampus: Inad-equate explanation for high extracellular glutamate during seizures. Neurobiol Dis. 2006 Nov 15; [Epub ahead of print]

9. Bjaalie JG, Leergaard TB (2006) Three-dimensional computerized reconstruction from serial sections: cell populations, re-gions, and whole brain. In: ‘Neuroana-tomical tract tracing: Molecules, neurons and systems’, 3rd edition (eds. L Zaborszky, FG Wouterlood, and JL Lanciego) pp. 530-565. Springer/Kluwer/Plenum

10. Bjaalie JG, Leergaard TB, Pettersen C (2006) Micro3D: computer program for three dimensional reconstruction visualiza-tion, and analysis of neuronal populations and brain regions. Int J Neurosci. 116:515-40.

11. Bjaalie JG, Zilles K (2006) New article category in anatomy and embryology: Methodological standards. Anat Embryol (Berl) 211:255.

12. Boy J, Leergaard TB, Schmidt T, Odeh F, Bichelmeier U, Nuber S, Holzmann C, Wree A, Prusiner SB, Bujard H, Riess O, Bjaalie JG (2006) Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models. Neuroimage 33:449-62.

13. Bragg AD, Amiry-Moghaddam M, Ottersen OP, Adams ME, Froehner SC (2006) As-sembly of a perivascular astrocyte protein scaffold at the mammalian blood-brain barrier is dependent on alpha-syntrophin. Glia 53:879-90.

14. *Davidsen T, Tonjum T (2006) Meningo-coccal genome dynamics. Nature Rev Mi-crobiol 4:11-22. Review. (Impact 14)

15. Davidsen, T., Ambur , Tønjum T (2006) Transformation and DNA repair. In: Frosch, M. & Maiden, M. Handbook of meningococci. WILEY-VCH Verlag Bonn Inc. ISBN 3-527-31260-9, pp. 119-144.

16. *D’Errico M, Parlanti E, Teson M, de Jesus BM, Degan P, Calcagnile A, Jaruga P, Bjo-ras M, Crescenzi M, Pedrini AM, Egly JM, Zambruno G, Stefanini M, Dizdaroglu M, Dogliotti E (2006) New functions of XPC in the protection of human skin cells from oxidative damage. EMBO J 25:4305-15. (Impact 7.7)

17. Dietrichs E, Gundersen V (2006) Gluta-mate--the most important transmitter in the brain. Tidsskr Nor Laegeforen, 126, 2643.

18. Eid T, Hammer J, Runden-Pran E, Roberg B, Thomas MJ, Osen K, Davanger S, Laake P, Torgner IA, Lee TS, Kim JH, Spencer DD, Ottersen OP, de Lanerolle NC (2006) Increased expression of phosphate-activat-ed glutaminase in hippocampal neurons in human mesial temporal lobe epilepsy. Acta Neuropathol (Berl). 2006 Nov 18; [Epub ahead of print]

19. Falnes PO, Klungland A, Alseth I (2006) Repair of methyl lesions in DNA and RNA by oxidative demethylation. Neuroscience. 2006 Dec 15; [Epub ahead of print]

20. Feligioni M, Holman D, Haglerod C, Da-vanger S, Henley JM (2006) Ultrastruc-tural localisation and differential agonist-induced regulation of AMPA and kainate receptors present at the presynaptic active zone and postsynaptic density. J Neuro-chem 99:549-60.

21. *Frydenlund DS, Bhardwaj A, Otsuka T, Mylonakou MN, Yasumura T, Davidson KG, Zeynalov E, Skare O, Laake P, Haug FM, Rash JE, Agre P, Ottersen OP, Amiry-Moghaddam M (2006) Temporary loss of perivascular aquaporin-4 in neocortex

after transient middle cerebral artery oc-clusion in mice. Proc Natl Acad Sci U S A 103:13532-6. (Impact 10.4)

22. Frye SA, Assalkhou R, Collins RF, Ford RC, Petersson C, Derrick JP, Tonjum T (2006) Topology of the outer-membrane secretin PilQ from Neisseria meningitidis. Microbiology. 152:3751-64.

23. *Fujimura N, Vacik T, Machon O, Vlcek C, Scalabrin S, Speth M, Diep D, Krauss S, Kozmik Z (2006) .Wnt-mediated downreg-ulation of Sp1 target genes by a transcrip-tional repressor Sp5. J Biol Chem . 2006 Nov 6. (Impact 7.66)

24. Golovanov AP, Balasingham S, Tzitzilo-nis C, Goult BT, Lian LY, Homberset H, Tonjum T, Derrick JP (2006) The solution structure of a domain from the Neisseria meningitidis lipoprotein PilP reveals a new beta-sandwich fold. J Mol Biol. 364:186-95.

25. Golovanov AP, Balasingham S, Tzitzilonis C, Goult BT, Lian LY, Homberset H, Ton-jum T, Derrick JP (2006) Assignment of (1)H, (13)C, and (15)N resonances for the PilP pilot protein from Neisseria meningiti-dis. J Biomol NMR 36 Suppl 5:68.

26. *Holen T (2006) Efficient prediction of siR-NAs with siRNArules 1.0: an open-source JAVA approach to siRNA algorithms. RNA 12:1620-5. (Impact 6.1)

27. Holmseth S, Lehre KP, Danbolt NC (2006) Specificity controls for immunocytochem-istry. Anat Embryol (Berl) 211:257-66.

28. Kleppa L, Kanavin OJ, Klungland A, Strom-me P (2006) A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome. Neuroscience. 2006 Nov 1; [Epub ahead of print]

29. Klungland A, Bjelland S (2006) Oxidative damage to purines in DNA: Role of mam-malian Ogg1. DNA Repair (Amst). 2006 Nov 24; [Epub ahead of print]

30. Klungland A, Laerdahl JK, Rognes T (2006) OGG1: from structural analysis to the knockout mouse. In Oxidative Damage to Nucleic Acids (Eds. Evans and Cooke), Landes Bioscience.

31. Lancaster B, Hu H, Gibb B, Storm JF (2006) Kinetics of ion channel modulation by cAMP in rat hippocampal neurones. J Physiol 576:403-17.

32. Larsen E, Meza TJ, Kleppa L, Klungland A (2006) Organ and cell specificity of base excision repair mutants in mice. Mutat Res. 2006 Jun 9; [Epub ahead of print]

33. *Larsen E, Reite K, Nesse G, Gran C, See-berg E, Klungland A (2006) Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1-/- mice. Oncogene 25:2425-32. (Impact 6.8)

16

Scientific journals Impact factor > 6

34. *Larsen KE, Schmitz Y, Troyer MD, Mosharov E, Dietrich P, Quazi AZ, Savalle M, Nemani V, Chaudhry FA, Edwards RH, Stefanis L, Sulzer D (2006) Alpha-synucle-in overexpression in PC12 and chromaf-fin cells impairs catecholamine release by interfering with a late step in exocytosis. J Neurosci, 26, 11915-22. (Impact 7.5.)

35. Leergaard TB, Lillehaug S, De Schutter E, Bower JM, Bjaalie JG (2006). Topographi-cal organization of pathways from somato-sensory cortex through the pontine nuclei to tactile regions of the rat cerebellar hemi-spheres. Eur J Neurosci. Nov;24(10):2801-12.

36. Lærdahl JK, Civcir PU, Bache-Andreassen L, Uggerud E (2006) Nucleophilic identity substitution reactions. The reaction be-tween hydrogen fluoride and protonated alkyl fluorides. Org Biomol Chem, 4, 135-41.

37. Mathiisen TM, Erlend Arnulf Nagelhus, Bahareh Jouleh, Reidun Torp, Didrik Sølie Frydenlund, Maria-Niki Mylonakou, Mah-mood Amiry-Moghaddam, Luciene Covo-lan, Jo Kristian Utvik, Bjørg Riber, Karen Marie Gujord, Jorunn Knutsen, Øivind Skare, Petter Laake, Svend Davanger, Finn-Mogens Haug, Eric Rinvik, and Ole Petter Ottersen (2006) Postembedding Immunogold Cytochemistry of Membrane Molecules and Amino Acid Transmitters in the Central Nervous System 72 – 108. In: Neuroanatomical Tract-Tracing 3 Mol-ecules, Neurons, and Systems (Edited by Laszlo Zaborszky), pp. 72-108. Springer.

38. Nakken S, Alseth I, Rognes T (2006) Computational prediction of the effects of non-synonymous single nucleotide poly-morphisms in human DNA repair genes. Neuroscience. 2006 Oct 19; [Epub ahead of print]

39. Nase G, Helm PJ, Reppen T, Ottersen OP (2006) A multi photon laser scanning mi-croscope setup for trans-cranial in vivo brain imaging on mice. Review of Scientific Instruments 76:123702-1 - 123702-5.

40. O’Shea RD, Lau CL, Farso MC, Diwakarla S, Zagami CJ, Svendsen BB, Feeney SJ, Callaway JK, Jones NM, Pow DV, Danbolt NC, Jarrott B, Beart PM (2006) Effects of lipopolysaccharide on glial phenotype and activity of glutamate transporters: Evidence for delayed up-regulation and redistribu-tion of GLT-1. Neurochem Int 48:604-10.

41. Persson S, Boulland JL, Aspling M, Lars-son M, Fremeau RT Jr, Edwards RH, Storm-Mathisen J, Chaudhry FA, Broman J (2006) Distribution of vesicular glutamate transporters 1 and 2 in the rat spinal cord, with a note on the spinocervical tract. J Comp Neurol 497:683-701.

42. Petersen PH, Tang H, Zou K, Zhong W (2006) The enigma of the numb-Notch re-lationship during mammalian embryogen-esis. Dev Neurosci 28:156-68.

43. Puwarawuttipanit W, Bragg AD, Fryden-lund DS, Mylonakou MN, Nagelhus EA, Peters MF, Kotchabhakdi N, Adams ME, Froehner SC, Haug FM, Ottersen OP, Amiry-Moghaddam M (2006) Differential effect of alpha-syntrophin knockout on aquaporin-4 and Kir4.1 expression in reti-nal macroglial cells in mice. Neuroscience 137:165-75.

44. Ranneberg-Nilsen T, Bjoras M, Luna L, Slettebakk R, Dale HA, Seeberg E, Rollag H (2006) Human cytomegalovirus infec-tion modulates DNA base excision repair in fibroblast cells. Virology 348:389-97.

45. Rash JE, Davidson KG, Kamasawa N, Yas-umura T, Kamasawa M, Zhang C, Michaels R, Restrepo D, Ottersen OP, Olson CO, Nagy JI (2005) Ultrastructural localization of connexins (Cx36, Cx43, Cx45), gluta-mate receptors and aquaporin-4 in rodent olfactory mucosa, olfactory nerve and ol-factory bulb. J Neurocytol. 2005 34:307-41. Epub 2006 Jul 13.

46. *Ringvoll J, Nordstrand LM, Vagbo CB, Talstad V, Reite K, Aas PA, Lauritzen KH, Liabakk NB, Bjork A, Doughty RW, Falnes PO, Krokan HE, Klungland A (2006) Re-pair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA. EMBO J 25:2189-98. (Impact 7.7)

47. Rødland EA (2006) Pseudoknots in RNA secondary structures: representation, enu-meration, and prevalence J Comput Biol 13:1197-213.

48. Rødland EA (2006) Exact distribution of word counts in shuffled sequences Advanc-es in Applied Probability, 38, 116-133.

49. Rødland EA (2006) Simes’ procedure is ‘valid on average’ Biometrika 93:3.

50. Sailer CA, Kaufmann WA, Kogler M, Chen L, Sausbier U, Ottersen OP, Ruth P, Shipston MJ, Knaus HG (2006) Immuno-localization of BK channels in hippocam-pal pyramidal neurons. Eur J Neurosci. 24:442-54.

51. *Sundheim O, Vagbo CB, Bjoras M, Sousa MM, Talstad V, Aas PA, Drablos F, Krokan HE, Tainer JA, Slupphaug G (2006) Hu-man ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J 25:3389-97. (Im-pact 7.7)

52. Thomassen GO, Rosok O, Rognes T (2006) Computational Prediction of MicroRNAs Encoded in Viral and Other Genomes. J Biomed Biotechnol 2006:95270.

53. Torp R, Singh PB, Sorensen DR, Dietrichs E, Hirschberg H (2006) Growth factors as neuroprotective treatment in Parkinson disease? Tidsskr Nor Laegeforen 126:899-901.

54. Touati E, Michel V, Thiberge JM, Ave P, Huerre M, Bourgade F, Klungland A, La-bigne A (2006) Deficiency in OGG1 pro-tects against inflammation and mutagenic effects associated with H. pylori infection in mouse. Helicobacter 11:494-505.

55. *Vervaeke K, Hu H, Graham LJ, Storm JF (2006) Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing. Neuron 49:257-70. (Impact 16.6)

56. Vervaeke K, Gu N, Agdestein C, Hu H, Storm JF (2006) Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol 576:235-56

57. *Vicente M, Hodgson J, Massidda O, Ton-jum T, Henriques-Normark B, Ron EZ (2006) The fallacies of hope: will we dis-cover new antibiotics to combat pathogen-ic bacteria in time? FEMS Microbiol Rev 30:841-52. Review. (Impact factor 10)

58. Walberg M, Mork C, Sandven P, Jorde AT, Bjoras M, Gaustad P (2006)18S rDNA polymerase chain reaction and sequencing in onychomycosis diagnostics. Acta Derm Venereol 86:223-6.

59. *Warskulat U, Borsch E, Reinehr R, Heller-Stilb B, Monnighoff I, Buchczyk D, Don-ner M, Flogel U, Kappert G, Soboll S, Beer S, Pfeffer K, Marschall HU, Gabrielsen M, Amiry-Moghaddam M, Ottersen OP, Dienes HP, Haussinger D (2006) Chronic liver disease is triggered by taurine trans-porter knockout in the mouse. FASEB J 20:574-6. (Impact 7.1)

60. Aas FE, Egge-Jacobsen W, Winther-Lars-en HC, Løvold C, Hitchen PG, Dell A, Koomey M (2006) Neisseria gonorrhoeae type IV pili undergo multisite, hierarchical modifications with phosphoethanolamine and phosphocholine requiring an enzyme structurally related to lipopolysaccharide phosphoethanolamine transferases. J Biol Chem, 281, 27712-23.

61. *Aas FE, Winther-Larsen HC, Wolfgang M, Frye S, Løvold C, Roos N, van Putten JP, Koomey M (2007) Substitutions in the N-terminal alpha helical spine of Neisseria gonorrhoeae pilin affect Type IV pilus as-sembly, dynamics and associated functions. Mol Microbiol, 63, 69-85. (Impact 6.2)

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ROGNES• Bioinformatics• Sequence analysis• Sequence database access• Protein 3D structure analysis

• Supercomputing facilities, Norwegian High performanceComputing Consortium (NOTUR)

• Databasing Centre-generated data

CENTRE OUTPUT• Publications in refereed journals• Weekly updated web-page• Centre Database• Ad hoc press releases• Commentaries in leading journals• Graduate and postgraduate training• Improved clinical diagnostics and treatment• Commercial exploitation, patents and licences

IMAGENE network MARIE CURIE Training Site

EU EU

EU

EU

EU

EU

EU

EU

EU

Groups with expertise in bio- and neuroinformatics

Groups with primary expertise in DNA repair mechanisms,molecular genetics tools, transgene production and proteo-mics

Groups that together command the full range of methodo-logies for functional, morphological, and biochemical analy-ses of central neurons

Groups that provide expertise on prokaryotic biology andcomparative genomics

BJAALIE• Neuroinformatics • Computerized microscopy

and automatic data acquisition• 3-D imaging and quantitative

analysis• Support for Centre Databases

BJØRÅS• Molecular biology• DNA repair mechanisms• Bioinformatics• Protein puri�cation*

• Biosensor technology*

• 3D protein structure*

KLUNGLAND• Production of transgenics and

knockouts• Mice models for DNA repair• Proteomics

KRAUSS• Molecular genetic tools for

regional selective manipulationof protein expression

• Stem cells

STORM• Cellular neurophysiology• Ion channels• Electrophysiology/Patch clamp• Live cell imaging/Ca2+imaging• Computer modeling• Behavioural analysis

OTTERSEN• High resolution EM and LM

imaging of membrane proteins• Live cell imaging of membrane

proteins• Organotypical culture models• Protein targeting and tra�cking

STORM-MATHISEN• Immunocytochemistry• Molecular & cell biology

(with Chaudhry)• Oocyte/voltage clamp• Transport imaging• In vitro/heterologous models

DANBOLT• Membrane protein & lipid

biochemistry/puri�cation• Liposome techniques• Transport mechanisms• Antibody production

KOOMEY• Manipulation of gene

expression in prokaryotes• Genome data mining• Translocation of macro-

molecules

TØNJUM• Molecular characterization of

membrane proteins and DNAbinding proteins

• Construction of mutants andchimeras

• Comparative genomics

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Rikshospitalet-Radiumhospitalet

Faculty of MedicineFaculty of mathe-

matics and naturalsciences

University of Oslo

The Research Council of Norway

Dept. of Molecular Biology,Inst. of Medical Microbiology

ExternalFunding

ExternalFunding

Institute of MolecularBiosciences

Institute of Basic Medical Sciences

Faculty division (RH)

Management and organizationThe Centre was in 2006 led by Ole Pet-ter Ottersen (Director) and Tone Tønjum (Assistant Director). Peder Heyerdahl Utne was the administrative leader. The Centre has a Steering Group who meets on a regular basis. This group consists of the eleven group leaders of the consor-tium.

For 2006 the Centre’s activities were mainly located in DOMUS MEDICA and the Research Building at RR, at Gaustad. The groups led by Krauss, Koomey, and Rognes are located on other premises in and around the University Campus.

The boardThe Board is responsible for ensuring that CMBN is developed in accordance with the current research plan. The members are:

Prof. Ole M. Sejersted, University of Oslo (Chairman) Director Prof. Olli A. Jänne, Biomedicum Helsinki, Finland Director Per Morten Vigtel, Norsk Investorforum Strategy Director Stein Vaaler, Rikshospitalet-RadiumhospitaletHead of Department Peter Gaustad, Rikshospitalet-RadiumhospitaletProfessor Borghild Roald, University of Oslo

Research groupsThe Centre consists of 11 research groups at the University of Oslo (UiO) and Rik-shospitalet-Radiumhositalet Medical Centre. In 2006 Trygve Leergaard was appointed as group leader with respon-sibility for NeSys – Neural systems and grahics Computing Laboratory, during the leave of absence of Jan G. Bjaalie. In total, more than 157 people are in-volved in the research at CMBN. The 11 groups of the CMBN are presented on the following pages.

ABOUT CMBN AND THE GROUPS

The Centre for Molecular Biology and Neuroscience (CMBN) at the University of Oslo (UiO) and Rikshospitalet-Radiumhospitalet Medical Centre (RR) is a Norwegian Centre of Excellence, appointed by the Research Council of Norway. The Centre`s main activities are located at Gaustad, in two adjacent buildings belonging to the University and RR, respectively.

Objectives The Centre shall take on a leading role in elucidating the role of DNA repair and genome maintenance mechanisms in preventing neurological disease and brain ageing. The Centre will develop and apply stem cell technology and targeted repair to broaden the range of therapeutic strategies in neurological disease. The centre will also investigate the processes that are upstream of DNA damage in nerve cells and will explore the excitotoxic hypothesis which holds that DNA damage may be caused by over-stimulation of glutamate receptors and subsequent formation of oxygen radicals. Progress in this field will require a better understanding of the function and molecular organization of the glutamate synapse.

ABOUT CMBN AND THE GROUPS

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Laboratory of Cellular Neurophysiology and Ion

channel functionAboutOur group is interested in brain function, from molecules to behavior. We study fundamental principles and mechanisms of neuronal signalling in the mammalian brain, and the roles of ion channels in behaviour, brain function, and disease. We focus on the functions of ion channels, in particular K+ channels, in central neurons and circuits, mainly in the hippocampus and

cerebral cortex.

Methods: Electrophysiological and optical recordings in brain slices and in vivo, molecular genetic and pharmacological manipulations, computational modelling,

and behavioural tests.

Challenges• To determine the functional roles and interplay of multiple signaling mechanisms

and ion channel types within different neuronal compartments and within the entire neuron.

• To elucidate functional roles of specific neuronal populations, signaling mechanisms and ion channel types, in active neuronal networks, and in the brain of behaving animals.

• To elucidate the roles of neuronal signaling mechanisms in ageing and neurological disease, including neurodegenerative and ischemic disorders, epilepsy, and memory disorders.

Projects•The roles of Kv7/KCNQ/M- and h/HCN-type K+ channels in neuronal signalling,

brain oscillations, synaptic plasticity, cognitive functions and epilepsy.

•The roles of Ca2+-activated K+ channels (BK and SK channels) in neuronal signalling, synaptic plasticity, cognitive functions, motor control, epilepsy and neuroprotection.

•The roles of voltage-gated ion channels in neuronal signalling, synaptic plasticity, learning and memory.

•Changes in neuronal signalling during ontogenetic development and ageing.

Recent achievements: Discovered that Kv7/M/KCNQ-type K+ channels are present in the perisomatic region but not in the apical dendrites of hippocampal pyramidal neurons (Hu et al., J. Neuroscience, 2007). Discovered that the persistent sodium current, INaP, paradoxically amplifies after hyperpolarizations and reduces the frequency (f/I) gain, and strongly modulates spike timing (Vervaeke et al., Neuron 2006); that Kv7/M/KCNQ-type K+ channels but not SK channels are essential for excitability control in hippocampal neurons (Gu et al., J Physiol, 2005); that Kv7/M/KCNQ-type K+ channels are essential for spatial learning and prevention of epilepsy (Nature Neuroscience 8: 51-60, 2005), that KCa1/BK-type K+ channels are essential for cerebellar learning and motor control (Proc Natl Acad Sci USA 101: 0474-8, 2004), the role of postsynaptic voltage-gated K+ channels in regulation of synaptic plasticity (LTP) and integration (Proc Natl Acad Sci USA 99:10144, 2002); that Kv7/M/KCNQ-type K+ channels are essential for intrinsic theta resonance in hippocampal neurons (J Physiol 545:783, 2002).

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Prof. Johan F. StormDept. of Physiology and Centre for Molecular Biology and Neuroscience | University of Oslo | POBox 1103 Blindern | N-0317 Oslo | Norwayjstorm@basalmed.uio.no | Phone: +47 22 85 12 46 | Fax: +47 22 85 12 49 | http://folk.uio.no/jstorm

20

About The Laboratory for Molecular Neuroscience investigates molecular mechanisms involved in the development of acute and chronic neurodegenerative disease, with a focus on the role of glutamate excitotoxicity. It aims at unravelling the molecular basis for cell death and edema development in stroke and other neurological conditions, and explores the pathophysiology of Alzheimer’s disease and temporal lobe epilepsy. Long term goals are to identify new molecular targets for neuroprotective strategies in stroke and other conditions involving glutamate excitotoxicity and to unravel the physiological and pathophysiological roles of astrocyte endfeet.

ChallengesNeurology continues to lag behind other disciplines when it comes to the range and efficacy of therapeutic strategies. In particular, common neurological conditions such as stroke, Alzheimer’s disease, and other acute or chronic neurodegenerative diseases call for new therapeutic strategies. Several of these conditions are particularly prevalent among the elderly and will constitute a growing health concern as the population ages. The challenge is to identify new principles of treatment for these diseases.

Projects• Assessing the role of water channel molecules (aquaporins) in the development of

brain edema and in the regulation of ion homeostasis in brain extracellular fluid.

• Exploration of the composition and function of the protein complexes that interact with glutamate receptors and that mediate downstream signalling from these.

• Unravelling the synaptic expression of kainate, NMDA, and AMPA receptors and the mechanisms responsible for their turnover.

• Identification of mechanisms underlying loss of glutamate homeostasis in temporal lobe epilepsy.

• Exploration of mechanisms involved in the formation of beta-amyloid in aging and Alzheimer’s disease

Recent achievements: Resolving modes of NMDA and AMPA receptor expression in hippocampal spine synapses (Nature Neuroscience 2:618-624, 1999). Identification of principles underlying expression and regulation of the water channel aquaporin-4 in the CNS (J Neurosci 17:171-80, 1997; J Neurosci 21:3045-51, 2001; PNAS 98:14108-13, 2001). Showing that removal of perivascular aquaporin-4 protects against development of postischemic edema and delays K+ clearance from the extracellular space (PNAS 100:2106-11, 2003; PNAS, 100:13615-20, 2003, Nature Reviews Neuroscience, 4:991-1001, 2003). Identification of neuronal plasma membrane microdomains that colocalize beta-amyloid and presenilin (Neuroscience, 120:291-300, 2003). Demonstrating loss of glutamine synthetase and perivascular aquaporin-4 in patients with temporal lobe epilepsy (Lancet, 363:28-37, 2004; PNAS 102:1193-8, 2005). Unravelling the molecular organization and function of astrocyte endfeet (PNAS 102: 8030-5, 2005; PNAS 103: 13532 – 6, 2006).

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Prof. Ole P. OttersenDept. of Anatomy and Centre for Molecular Biology and Neuroscience | University of Oslo | POBox 1105 Blindern | N-0317 Oslo | Norway o.p.ottersen@medisin.uio.no | Phone: +47 90 13 26 10 | Fax: +47 22 85 12 99 | http://www.cmbn.no/ottersen

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The Synaptic Neurochemistry Laboratory

About Main interests are the mechanisms underlying synaptic transmission: localization,

transport, synthesis, release, action and breakdown of neurotransmitters (glutamate, aspartate, GABA, glycine, monoamines, acetylcholine). These mechanisms are studied in normal and pathological conditions, and during ontogenetic development and ageing.

ChallengesRecent research by our group has opened possibilities for studying in depth aspects of nervous system functions in health and disease. An important aspect is how nerve endings provide glutamate for synaptic release and how they recover released glutamate for reuse. Thus the molecular identification and characterization of glutamine transporters, SN (Cell 1999, EMBO J 2001, Eur J Neurosci 2002, Glia 2003, J Am Soc Nephrol 2005) and SA/SAT (PNAS 2000, J Neurosci 2002, J Cell Biol 2002), and the ultrastructural localization of monocarboxyltate transporters (Cereb Cortex 2005) provide new approaches to understanding synaptic function. The identification of proteins, VGLUT1-3 (Neuron 2001, PNAS 2002), that pump glutamate into synaptic vesicles allows the packaging of the transmitter to be characterised (J Comp Neurol 2004, 2006) and modified (Science 2004). The observation that even astrocytes (Nature Neurosci 2004, 2007) and neuroendocrine cells (J Cell Sci 2004) can release neurotransmitter amino acids in a way resembling synaptic release, together with findings that glutamate and other neuroactive substances can be co-released from nerve endings (Eur J Neurosci 2003, Molec Neurosci 2004), and that oligodendrocytes have NMDA receptors (Nature 2005), suggests novel ways of intercellular communication.

Projects• The role of glutamine, and other metabolic precursors of glutamate, for keeping

up synaptic release. Transporters and metabolising enzymes are located immunocytochemically and their functional roles studied in oocytes and cultured cells by artificial expression, and in animals with modified or blocked expression of the specific genes.

• Interplay of glutamate with e.g. aspartate, GABA or glycine at brain synapses and endocrine cells. Localisation of the amino acids and their transporters, receptors and enzymes in normal and experimentally modified animals, ie animal models of neurological disease (e.g. epilepsy), including knock-out mice.

• Synaptic changes during ontogenetic development and in animals with deficient DNA repair.

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Prof. Jon Storm-Mathisen / Dr. Linda H. Bergersen / Dr. Farrukh A. Chaudhry / Dr. Vidar GundersenDept Anatomy and Centre for Molecular Biology and Neuroscience | University of Oslo | P.O. Box 1105 Blindern | N-0317 Oslo | Norwayjonsm@medisin.uio.no / l.h.bergersen@medisin.uio.no / f.a.chaudhry@biotek.uio.no/ vidar.gundersen@medisin.uio.noPhone: +47 22 85 12 58 / +47 22 85 14 96 / +47 22 84 05 65 | Fax +47 22 85 12 78 http://folk.uio.no/jonsm/ | http://www.cmbn.no/group-storm-mathisen.html

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AboutThe Group studies how transporter proteins (in normal and diseased brains of different ages) modulate the extracellular spatiotemporal concentration profiles of excitatory (glutamate and aspartate) and inhibitory (GABA and glycine) transmitter amino acids. The transporters studied are those able to transport aspartate, GABA, glutamate, glycine and monoamines across brain plasma membranes. These include the glutamate (EAAT1-5), GABA (GAT1-4), glycine (GLYT1-2), dopamine (DAT) and dicarboxylate (SDCT2) transporters as well as the glutamate-cystine exchanger and their anchoring and regulatory proteins.

ChallengesThe human genome contains about 300 different transporter protein genes. Many of the encoded transporters, including those for glutamate, are subject to sophisticated dynamic regulation, and are also ion channels in addition to being transporters. Thus, the transporters appear to have more refined functions than just being pumps, but these functions are poorly understood. The overall aim of the Group is to determine the roles of the individual transporter subtypes in order to better understand normal physiology and disease, and to uncover new therapeutic opportunities. Disturbed control of extracellular glutamate appears to be an important factor, directly or indirectly, in all neurological disorders as well as in drug abuse and major psychiatric disorders (e.g. schizophrenia), as a consequence of the abundance of glutamate, the ubiquitous presence of glutamate receptors, and the interplay between glutamate, oxidation and energy metabolism (for review see: Danbolt, 2001: Prog. Neurobiol).

Projects• Production of suitable tools (including antibodies) and model systems (including

gene modified animals)

• Determination of transporter distributions and densities around select synapses in normal adult brains and how these parameters change during development, ageing, drug use and disease

• Computer modelling of transmitter release, diffusion, removal and receptor activation

• Transporter protein purification, reconstitution and crystallisation

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Prof. Niels Chr. Danbolt Dept. of Anatonomy & Centre for Molecular Biology and Neuroscience | University of Oslo | P.O. Box 1105 Blindern | N-0317 Oslo | Norway n.c.danbolt@basalmed.uio.no | Phone: +47 22 85 12 60 / +47 22 85 10 41 | Fax: +47 22 85 12 78 | www.neurotransporter.org

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NeSys – Neural systems and graphics Computing

LaboratoryAboutNeSys is a computational neuroanatomy and neuroinformatics laboratory. The research of the group focuses on 1) the development of new and powerful methods for computerized data acquisition, 3-D reconstruction, visualization

and quantitative analyses of features in brain tissues, 2) data management and construction of 3-D brain atlases of experimental data, and 3) investigations on

organization and re-organization of brain systems architecture in rat and mouse models, and 4) in vivo imaging in the context of multi-modality brain atlasing.

ChallengesMuch of the research carried out today on rodent models generates high resolution image data, allowing characterization and analysis of brain molecular distribution, gene expression, and connectivity. It is of great importance not only to record more data but also to integrate data, re-use data in novel combinations, and perform more powerful analyses. To this end, data management systems and advanced analytical tools are needed. Structure and structure-function relationships are often better understood by introducing 3-D reconstruction and advanced visualization and modelling tools.

Projects1. Neuroscience databases and atlasing systems. We develop database applications for image data, from microscopy level to in vivo imaging data. We now host a rat and mouse brain work bench (www.rbwb.org), providing access to repositories, databases, and analytical tools, for circuit level as well as molecular distribution data.

2. Localization in the brain. We develop and use technologies (robotic microscopy data acquisition, computerised 3-D reconstruction, and digital atlasing) for efficiently assigning localization to neuroscience data.

3. Brain map transformations. We study design principles and changes in the architecture of major circuits in the brain following external and genetic manipulations.

4. High resolution MRI and microPET. In several project collaborations, tomographical imaging techniques are employed to characterize structural and functional relationships occurring in the brain following experimental perturbations or disease.

Recent achievements1.) Development and sharing of software for 3-D reconstruction, visualization, and analysis of neuronal distribution and brain regional organization (www.rodentbrainworkbench.org). 2.) Development of a novel digital atlas system for evaluation of cellular distribution patterns in large series of high-resolution mosaic images of histological sections (Boy et al., NeuroImage 2006; 33: 449-462, www.rodentbrainworkbench.org). 3.) Mapping of topographical organization in cerebro-cerebellar pathways from somatosensory cortex through the pontine nuclei to different locations in the cerebellum (Odeh et al., J Neurosci. 2005; 25: 5680-5690; Leergaard et al., Eur J Neurosci. 2006; 24: 28012812). 4.) Establishment of the first database on Functional Anatomy of the Cerebro-Cerebellar System in rat (Bjaalie et al., Neuroscience 2005; 136:681-696; Moene et al., Neuroinformatics 2007, In Press; www.rodentbrainworkbench.org).

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Dr. Trygve B. Leergaard / Prof. Jan G. BjaalieDept. of Anatomy and Centre for Molecular Biology and Neuroscience | University of Oslo | P.O. Box 1105 Blindern | N-0317 Oslo | Norwayt.b.leergaard@medisin.uio.no / j.g.bjaalie@basalmed.uio.no | Phone: +47 22 85 10 52 / +47 22 85 12 63 | Fax: +47 22 85 10 45 | www.nesys.uio.no

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AboutThe Bioinformatics group uses computational methods to analyse genome sequences, amino acid sequences, and gene expression data, both to identify new genes of interest and to determine their function and role in the cell. Advanced statistical and computational tools are both being used and developed. The group is also creating databases and web sites with our tools and generated data. We are involved in many collaborative projects with different research groups.

ChallengesHuge amounts of molecular biology data is being generated from a range of different technologies. Complete genome sequences from hundreds and soon thousands of organisms are available. Data from many large-scale nucleic acid hybridization experiments, DNA polymorphism studies, molecular interaction experiments and protein structure determination projects is also publicly available. Apparently all this data should enable the extraction of much biological insight, but the main challenge in computational biology is to integrate and make sense of all the data. Computational analyses may be hard, but can be very powerful in many types of studies, saving a lot of work in the wet lab or permitting otherwise impossible studies.

Projects • Sequence similarity: Tools like PARALIGN for particularly rapid and sensitive

sequence database similarity searches have been developed. Parallel computing technology is exploited to get the highest performance. These tools are now being used to build gene homology networks and to cluster orthologous genes into groups.

• Comparative genomics and DNA repair: General sequence analysis and computational identification of new DNA repair genes is carried out in close collaboration with other groups. Both advanced homology based methods and comparative genomics methods are used. A web portal is being established with an underlying database containing information on DNA repair genes across species.

• Structural bioinformatics: Computational models of the 3D structure of proteins are created and studied in order to understand the molecular mechanisms of enzyme activities. Docking and molecular dynamics simulations are also used in our studies. Recently, we have started studies of the consistency of the structural conformation of very short segments of proteins.

• Non-coding RNA genes: The group is developing computational methods to identify new non-coding RNA genes (ncRNA), which are generally poorly annotated. The tool RNAmmer, based on hidden Markov models, is being developed to accurately locate ribosomal RNA genes in genomic sequences. Custom genome tiling microarrays have been designed to study transcription in “intergenic” regions.

• DNA variation: We are studying single nucleotide polymorphisms (SNPs) in DNA repair genes and selected other proteins. Certain DNA polymorphisms may cause disorders in individuals. How and where do polymorphisms in the human genome occur? Can we predict which polymorphisms are causing problems?

Recent achievementsCreated a rapid parallel implementation of the Smith-Waterman sequence alignment algorithm (Bioinformatics 2000) and developed the heuristic PARALIGN algorithm (NAR 2001). Identified skewed distribution of DNA uptake sequences in bacterial genomes (NAR 2004). Discovered a new protein superfamily that includes two novel alkylpurine DNA repair glycosylases (Mol. Microbiol. 2006), and analysed their mechanism of repair based on a structural model (NAR, in press).

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Associate professor Torbjørn RognesCentre for Molecular Biology and Neuroscience | Institute of Medical Microbiology | Rikshospitalet-Radiumhospitalet | NO-0027 Oslo | Norwaytorbjorn.rognes@medisin.uio.no | Phone: +47 90 75 55 87 or +47 22 84 47 87 | Fax: +47 22 84 47 82 | www.cmbn.no/rognes

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Laboratory for Genome repair and regulation

AboutErroneous methylation on the DNA molecule must be repaired. Such repair is

carried out by three completely different strategies. One of these strategies was only identified very recently, oxidative demethylation, and is performed by the

conserved AlkB protein. In mammals, 8 different AlkB homologs exist (ABH1-8). ABH2 has been shown to repair methylated genomic DNA in vivo (Ringvoll et

al., EMBO j 2006). The functions of the other homologs are still unknown; roles in post translational modifications of tRNA and protein demethylation (including histone)

have been proposed. Methylation is a widespread modification of DNA, RNA, and proteins. For many years such modification was considered to be irreversible, today it is established that regulated demethylation are vital for correct function of macromolecules. Numerous enzymes responsible for the introduction of methyl groups have been identified during the last two decades, but the first corresponding demethylating enzymes were identified recently. We generate gene-targeted mice lacking individual ABH genes in order to elucidate the in vivo role and biological roles of these homologs.

Challenges We use standard molecular biology strategies, including the construction of cells and animals lacking specific DNA repair functions, to identify and characterize gene-functions for repair and regulation of DNA, tRNA and histones. Several collaborations, internationally and within the Centre for Molecular Biology and Neuroscience, have been initiated.

ProjectsWe aim to identify the role of indivi